The alkaloids obtainable from Vinca rosea (Catharanthus rosea) have been a most productive source of drugs which adversely affect the growth of experimental malignancies in mammals. Initially, only some of the alkaloids obtained from the leaves of the plant by extraction and purified by chromatography were found to be active antineoplastic agents. It was found that these antineoplastic Vinca alkaloids were dimeric indole-dihydroindole alkaloids representable by the formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vinblastine (vincaleucoblastine, VLB) is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl, and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl or formyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine and leuroformine, respectively are represented. Literature references to the above alkaloids are as follows: leurosine (U.S. Pat. No. 3,370,057), VLB (U.S. Pat. No. 3,097,137), leuroformine (Belgian Pat. No. 811,110); leurosidine (vinrosidine) and leurocristine (to be referred to hereafter as vincristine) (both in U.S. Pat. No. 3,205,220).
Two of the above alkaloids, vinblastine and vincristine, are now marketed for the treatment of malignancies, particularly the leukemias and related diseases, in humans. The two marketed alkaloids are customarily administered by the iv route. Two others, leurosidine and leuroformine, have been on clinical trial in the U.S. or in Europe.
Chemical modification of the Vinca alkaloids started slowly for several reasons. In the first place, the molecular structures involved are extremely complex, and chemical reactions which modify one specific functional group of the molecule without affecting other groups have been difficult to develop. Secondly, dimeric alkaloids lacking desirable chemotherapeutic properties have been recovered or produced from Vinca rosea extracts, and a determination of their structures has led to the conclusion that these inactive compounds are closely related structurally to, or are even isomeric with, the active alkaloids.
One of the more recent, and more successful, modifications of the basic indole-dihydroindole structure has been the preparation of C-3 carboxamide and carboxhydrazide derivatives. Many of these carboxamides are active anti-tumor agents (see U.S. Pat. No. 4,166,810, Barnett et al. J. Med. Chem., 21 88 (1978) and Conrad et al., id, 22, 391 (1979). In particular, 4-desacetyl VLB C-3 carboxamide (vindesine) has proved to be very active in initial clinical tests and is currently on clinical trial in humans.
U.S. Pat. No. 4,029,663 discloses three anhydro derivatives each of 4-desacetylvinblastine and 4-desacetylvincristine. These derivatives were prepared by the action of cold concentrated sulfuric acid on vinblastine or vincristine respectively. Three different double bond isomers were formed in each case and were designated as, in the case of VLB, 3',4'-anhydro-4-desacetyl VLB; 4',20'-anhydro-4-desacetyl VLB (isomer 1); and 4',20'-anhydro-4-desacetyl VLB (isomer 2). The 4',20' isomers are double bond isomers in which the 21'-methyl is either above or below the plane of the vinblastine molecule.
Potier, Kutney and their associated research groups have prepared 3',4'-anhydrovinblastine by the use of a Polonovski fragmentation reaction involving the reaction of an N.sub.b -oxide of catharanthine with vindoline in the presence of trifluoroacetic acid--see, for example, J.C.S. Chem. Comm. 670 (1975); British Patent Specification No. 1,536,407; Tetrahedron Letters, 1099, 3945 (1976); U.S. Pat. No. 4,144,237; Heterocycles, 3, 205, 639 (1975), 6, 905 (1977).
Functionalization of the double bond in 3',4'-anhydrovinblastine has proved difficult. Recently, Potier and his research group have reported the successful conversion of this compound (called by them .DELTA..sup.15'(20') -dehydrovinblastine) to vinblastine. This work is summarized in an article appearing in J.A.C.S., 101, 2243 (1979).
Kutney et al., Can. J. Chem., 56, 62 (1978) has also functionalized the 3',4'-double bond of 3',4'-anhydiovinblastine by oxidation with OsO.sub.4 to produce leurosine.
20'-Hydroxy derivatives of 4-deacetyl vinblastine or other vinca alkoloids have not heretofore been reported, nor has derivatization of the 4',20'-anhydro-double bond in the 4',20'-anhydro 4-deacetyl VLB or vincristine isomers.